Purpose.The purpose of this Funding Opportunity
Announcement is to solicit applications from qualified investigators for the
establishment of a Hepatitis B Clinical Research Network. This network
will consist of up to 10 clinical center sites and a single data coordinating
center. Additionally, the network will be complemented with two
basic/translational research laboratories. A virology center and an
immunology center will both be integral to the consortium by providing support
for the scientific pursuits of the network.

The total amount to be awarded
and the anticipated number of awards. The NIDDK intends to commit
approximately $3,000,000 during FY 2008 (year 1 of the Network) and up to
approximately $7,000,000 per year in years 2 to 7 of the Network. It
is anticipated that the number of awards issued under this FOA will be: Up
to 10 clinical center (CC) site awards, one data coordinating center
(DCC), one virology center, and one immunology center. The number of
awards issued under this FOA is contingent upon the availability of funds
and the submission of a sufficient number of meritorious applications.

Because the nature and scope of
the proposed research will vary from application to application, it is
anticipated that the size and duration of each award will also vary. The
total amount awarded and the number of awards will depend upon the
mechanism numbers, quality, duration, and costs of the applications
received.

Eligible principal investigators
include individuals with the skills, knowledge, and resources necessary to
carry out the proposed research are invited to work with their institution
to develop an application for support. Individuals from underrepresented
racial and ethnic groups as well as individuals with disabilities are
always encouraged to apply for NIH support.

Applicants may submit more than
one application, provided they are scientifically distinct.

Number of PDs/PIs.More than
one PD/PI, or multiple PDs/PIs, may be designated on the application.

Nature of the research opportunity: The National
Institute of Diabetes and Digestive and Kidney Diseases of the National
Institutes of Health of the U.S. Department of Health and Human Services is
seeking applications to establish a Hepatitis B Clinical Research Network of
investigators for the purposes of promoting translational research on hepatitis
B focusing upon elucidating the pathogenesis and natural history and developing
means of treatment and control. The Network would be composed of up to 10
clinical centers with expertise in diagnosis and management of hepatitis B, a
Virology Center with laboratory expertise in the molecular virology of HBV, an
Immunology Center with expertise in the immunologic assays of cellular, humoral
and cytokine activities in relation to chronic hepatitis B, and a Data
Coordinating Center with expertise in the management of multicenter studies,
clinical and translational datasets.

This RFA requests four separate types of applications: up to
10 Clinical Centers, a single Data Coordinating Center, a single Virology Center and a single Immunology Center.

Background information: Chronic hepatitis B affects
approximately 350 million persons throughout the world, a significant
proportion of which are at risk for developing cirrhosis, liver failure, and
liver cancer. In the United States, approximately 1.5 million Americans,
or ~ 0.5% of the population have acquired the disease. Chronic hepatitis
B is uncommon in the “general” population, but affects certain
groups at a much higher rate. Thus, the prevalence of chronic hepatitis B
is estimated to be 3 to 5% among men who have sex with men, injection drug
users, renal dialysis patients and persons with hemophilia. Importantly,
chronic hepatitis B in the United States affects 10 to 15% of foreign born and
first generation Asian Americans and is also common among recent immigrants
from the Middle East, Africa and Eastern Europe. Approximately 5% of
children adopted from Asia, Russia and Eastern Europe have chronic hepatitis
B.

Therapy has recently advanced considerably with the
availability of 6 different agents to treat chronic hepatitis B (interferon
alpha, peginterferon, lamivudine, adefovir dipivoxil, telbuvidine and
entecavir) and several more likely to be approved in the near future (tenofovir
and emtricitabine). Each of these agents is effective; however, they do
not cure hepatitis B but rather lead to potent suppression of viral replication.
The majority of patients respond to treatment with improvements in liver
histology and serum aminotransferase levels, but almost all patients relapse
when therapy is stopped. Importantly, there are no reliable guidelines
for how these agents should be used: which agent? in which patient?
alone or in combination? for a defined period (1 yr, 2 yr) or
indefinitely? using what markers to measure success or
failure? Many patients are placed on an oral anti-HBV agent indefinitely, although the long-term efficacy and safety of most of these agents is
unproven.

A major shortcoming of current therapies is the development
of antiviral resistance. Antiviral resistance develops in ~ 20% of persons
treated with lamivudine and approximately 3% of those treated with adefovir
each year. The rate with entecavir is lower but long-term studies have
not been done. Ultimately a large proportion of patients develop
resistance, at which point the antiviral agent has little or no effect. At
present there is no standardization of definitions for resistance or resistance
testing. In addition, the long-term clinical significance of the
development of resistance is unclear. These are important issues that are
not likely to be addressed by phase III trials demonstrating efficacy of each
drug separately and with little or no follow up (success being defined as
improvements in viral levels, aminotransferase levels and histology at one year
while on therapy with no or incomplete information on what occurs once therapy
is stopped or with long-term treatment).

Scientific knowledge to be achieved: Several research
challenges remain regarding chronic hepatitis B despite the more than 40 years
of investigation. Basic questions regarding the immunologic factors that
interplay between the host and the hepatitis B virus in the progression of
acute to chronic hepatitis B or in the evasion of immune clearance; the
components of the host and virologic interactions that influence hepatocellular
injury; the determinants of liver disease progression versus quiescence;
determining which patients should be treated with which agent(s) for how long
and when to stop therapy on the basis of which criteria. These issues in
addition to several others were discussed during an NIH conference on the
Management of Chronic HBV: 2006 that was summarized in Hepatology 2007
Apr;45(4):1056-75. Other research priorities pertaining to viral
hepatitis B can be found in the previously published Trans-NIH Action Plan for
Liver Disease Research in the chapter on viral hepatitis (http://liverplan.niddk.nih.gov).

The Network would be charged with developing a large
database of patients with chronic hepatitis B and with the design of a
treatment protocol that would permit the development of testable hypotheses
that will address the most important clinical research challenges that should
be resolved in the next 5 to 10 years as delineated in the Management of
Chronic HBV: 2006 summary.

Objective of this research program: To promote translational
research on chronic hepatitis B focusing upon elucidating the pathogenesis and natural history and developing means of treatment and control, the NIDDK proposes to
establish a Hepatitis B Clinical Research Network. The Network would
accelerate clinical research and progress in understanding the
immunopathogenesis of chronic hepatitis B and treatment strategies with the
currently available therapeutic agents.

Organization of the Hepatitis B Clinical Research Network:
The Hepatitis B Clinical Research Network will be a cooperative network of up
to 10 Clinical Centers (CC), one Data Coordinating Center (DCC), one Virology Center, and one Immunology Center. Clinical Centers will be responsible for
proposing protocols, participating in their overall development, conducting the
research, and disseminating research findings. All individual CCs, the Virology Center, and Immunology Center will be required to participate in a cooperative and
interactive manner with one another and with the DCC in all aspects of the
Hepatitis B Clinical Research Network. The Virology Center will be
responsible for developing and testing hypotheses regarding the role of viral
factors in the pathogenesis, course, and outcome of hepatitis B by utilization
of the patients enrolled in protocols. The Immunology Center will be responsible for developing and testing hypotheses regarding the role of the
immune system in the course and outcome of chronic hepatitis B and in
developing and performing state-of-the-art immunological assays on patients
enrolled in protocols. The DCC will support protocol development, provide
sample size calculations, statistical advice, questionnaires, and data
analysis; support manuscript preparation; organize committee meetings; and
provide overall study coordination and quality assurance, including
coordination of the logistical activities of the Data and Safety Monitoring
Board, the Steering Committee and other standing committees. Applicants for the
DCC should also propose central laboratory and virologic testing of clinical
specimens.

Governance: A Steering Committee will be the main governing
body of the Hepatitis B Clinical Research Network. At a minimum, the Steering
Committee will be composed of the principal investigators (or the corresponding
principal investigator of a multiple PI application) of each Clinical Center in the Network, the principal investigator of the DCC, the Virology and Immunology Centers and the NIDDK Project Scientist. The first meeting of the Steering
Committee will be convened by the NIDDK Project Scientist in conjunction with
the principal investigator of the DCC. By the end of the first or second
meeting of the Committee, the NIDDK will name a study Chairperson from one of
the Clinical Centers to oversee and guide Steering Committee activities.
The Steering Committee will meet as often as three to six times during the
first 12 months of the study, and two to four times per year thereafter.
All major scientific decisions will be determined by a majority vote of the
Steering Committee. Major decisions that have financial implications,
such as the final protocol, or safety implications, such as the choice of study
drugs will be made by the steering committee with final approval by the NIDDK.
Each Clinical Center, the Virology Center, the Immunology Center, the DCC, and
the NIDDK Project Scientist will have one vote. The Steering Committee
will have primary responsibility for the general organization of Hepatitis B Clinical Research Network,
finalizing common clinical protocols, facilitating the development of a
standardized nomenclature, diagnostic criteria, histological definitions, and
necessary components to the common database on patients. The Steering
Committee will be responsible for the conduct and monitoring of studies and
reporting study results. Topics for investigational and treatment
protocols will be proposed and prioritized by the Steering Committee.

For each investigational or therapeutic protocol, one Clinical Center will take the lead responsibility for drafting the protocol, although the
Steering Committee will provide input and will be responsible for assuring
development of a common protocol to be implemented by all of the CCs. All
clinical center principal investigators will be strongly encouraged to fully
commit their center resources and efforts to the Network protocols.

A Pathology Committee will supplement the activities of the
Steering Committee and will ensure a consistency of processing and
interpretation of liver biopsies. This committee will be composed of the
hepatic pathologist from each Clinical Center as well as a lead hepatic
pathologist who will be appointed by the NIDDK. The lead hepatic
pathologist will be either one of the hepatic pathologists from the Clinical Centers or the DCC, or an outside pathologist chosen specifically for this
task.

Other subcommittees of the Steering Committee will be
established as necessary. For example, a Publications Committee would be
helpful to facilitate the process for authorship selection and to supervise
preparation of manuscripts.

An independent Data and Safety Monitoring Board will be
established by the NIDDK to review protocols and monitor patient safety and
performance of each study. As a part of its responsibilities, the Data
and Safety Monitoring Board will submit recommendations to the NIDDK regarding
the continuation of each study.

Each investigational or therapeutic protocol will be
implemented in a minimum of two and optimally in all of the Clinical Centers, depending
on the number of patients and investigational expertise needed for the
study. As specific protocols are developed, support will depend on the
availability of funds and will be provided on a per patient basis. All
the Clinical Centers must be willing to pursue this funding arrangement for
each new protocol conducted.

Clinical protocols must be approved by local institutional
review boards and the Hepatitis B Clinical Research Network Data and Safety
Monitoring Board before initiation. The exact number of protocols
supported in the program will depend on the nature and extent of the
investigations proposed by the Steering Committee. Databases may be
developed; epidemiological studies and other clinical studies may be
performed. Planning may be done for large clinical trials that would be
submitted as separate R01s if further funding is necessary. The Hepatitis
B Clinical Research Network investigators are also encouraged to seek out
separate funding for special projects and to develop collaboration with
laboratory and basic research investigators to draw upon the resources
(clinical data, serum, tissue, DNA) made available by the Hepatitis B Clinical
Research Network Database. Any specific collaboration involving the
resources of the Hepatitis B Clinical Research Network will require approval by
the Steering Committee.

Research Scope: The objective of this RFA is to establish a
Hepatitis B Clinical Research Network that will accelerate advances in the
understanding and clinical management of this liver disease.

The Network would be charged with developing a large
database of all patients with hepatitis B followed at their centers with
special focus on newly diagnosed cases. The Network would also be charged with
developing standard nomenclature, diagnostic criteria and staging and grading
systems. The Network would be responsible for designing a prospective trial of
long-term therapy of hepatitis B and developing testable hypotheses regarding
pathogenesis in collaboration with primarily the Virology and Immunology Center
Principal Investigators or with outside research investigators. The
Network will be charged with developing a policy for ancillary studies that
complement the clinical characterization of patients, which might include studies
of immunologic responses, viral mutations and variants, and genetics. The
RFA would specify that Centers would be chosen in part on the basis of numbers
of patients with hepatitis B being seen and followed at their site, as well as
the racial/ethnic diversity of their population. The Virology Center will be charged with developing testable hypotheses from the main treatment protocol and
database such as viral mechanisms of pathogenesis, viral genotype-phenotype
comparisons, and HBV DNA mutation-resistance associations. The Immunology Center will be charged with testing immunopathogenesis hypotheses generated from
the main treatment protocol and database. Serum, DNA and tissue samples
would be stored in a central repository. Once established, funding of
ancillary studies would be offered through program announcements.

A central challenge to the Hepatitis B Clinical Research
Network will be to establish a randomized, controlled trial of long-term mono-
versus combination therapy for chronic hepatitis B. The Network steering
committee will formulate and design this trial which will be aimed at assessing
the long-term (4-5 year) efficacy of monotherapy versus combination therapy of
chronic hepatitis B. The Network will solicit industry partners to help
support this trial. Possible agents to be studied would include (but not be
limited to):

All projects must be completed within the 7-year duration of
this research program.

These are examples only. Applicants should not feel
limited to the subjects mentioned above and are encouraged to submit other
topics pertinent to the objective of the RFA. It is not the intent of the
Network to provide support for only one or two protocols that run for the
entire seven years. Multiple trials or clinical and epidemiological investigations
will be conducted, possibly two to four a year, some large and some
small. It is anticipated that in the initial one or two years, trials and
investigations will be selected from the studies proposed by the successful
Clinical Centers in their applications.

Each Clinical Center within the Network should propose a
research plan that includes the structure of a large database as well as a
clinical trial research protocol as a model that could be used in the Network
environment. The protocols should demonstrate knowledge of the disease
and its pathogenesis. Each protocol should require sufficient subjects to
necessitate the use of a Network with multicenter participation.
Applicants should indicate knowledge of the number of patients required for
each study based on sample size calculations. One protocol must be a
long-term study (four to five years) and the other protocol should be centered
upon the database to address a research challenge as delineated in the
Management of Chronic HBV: 2006 meeting summary or from the Trans-NIH Action
Plan for Liver Disease Research. For the overall structure and factors
that are included in the common database of patients include a justification
for necessary information on patients to be included. For each of the two
protocols include a description in approximately two pages of the rationale,
research aims, outcome measures, and study design. In addition, provide a
description of the proposed patient populations with an estimate of the
expected distribution of male and female patients, ages, and assurances of the
applicant's access to the patient populations.

The Clinical Center principal investigator should indicate
for each protocol how many patients meeting proposed criteria are available in
his/her Clinical Center and how many will be required from the entire Network
(all of the Clinical Centers). In the discussion of outcome measures, it
will be important to indicate appropriate objective measures of primary and
secondary outcome. The Clinical Center principal investigators are
encouraged to explore, within the context of their proposed protocols, new
technologies to monitor disease progression and response to therapy.
Funding for the relevant technology should be presently available for each protocol
proposed. It will also be important to include strategies to assure
adherence to therapy as part of the protocol.

The Virology and Immunology Centers should put forth
scientific proposals that are complementary and integrated with the patient
database and that will be able to leverage the understanding of the
pathophysiologic mechanisms from specimens collected from a proposed clinical
research protocol. As with the applications for Clinical Centers,
applications for the Virology and Immunology Centers should include a research
plan that would use samples and resources of the large patient database as well
as prospective clinical research protocols involving a Network
environment. The Virology and Immunology Centers should propose
hypotheses that could be tested with specialized virological or immunological
testing on serum, tissue or peripheral blood mononuclear cells from patients in
the database and clinical trials. The research plan should discuss sample
size calculations and be feasible within the 7 year time constraint. The
scientific proposal should demonstrate knowledge of the disease, its
pathogenesis, and address an area of research challenge with significant
clinical translational potential. A detailed research plan should be proposed
that will focus upon the viral and immunopathogenesis of chronic hepatitis
B. Proposals may address topics such as but not limited to: defining
early events during HBV infection; identifying new targets in viral replication
and the host for development of small molecule therapeutics; better
characterization of the viral-host interactions, basis for the generation and
stability of the cccDNA; and viral state of HBV in humans with different forms
of chronic hepatitis B (such as the inactive carrier state, the immune tolerant
phase of chronic hepatitis B, typical HBeAg-positive and HBeAg-negative chronic
hepatitis B, HBV related cirrhosis), better characterize and delineate the viral and immunological changes
that occur with antiviral therapy and that correlate with or determine outcome
of treatment .

This funding opportunity
will use the U01
cooperative agreement award mechanism(s).

As an applicant, you
will be solely responsible for planning, directing, and executing the proposed
project.

This funding opportunity
uses the just-in-time budget concepts. It also uses the non-modular budget
format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).
A detailed categorical budget for the "Initial Budget Period" and the
"Entire Proposed Period of Support" is to be submitted with the
application.

The NIH U01 is a cooperative
agreement award mechanism. In the cooperative agreement mechanism, the
Principal Investigator retains the primary responsibility and dominant role for
planning, directing, and executing the proposed project, with NIH staff being
substantially involved as a partner with the Principal Investigator, as
described under the Section VI. 2. Administrative
Requirements, "Cooperative Agreement Terms and Conditions of
Award".

2. Funds Available

The NIDDK intends to commit approximately three million dollars
in FY 2008to fund up to 13 new and/or competing continuation grants in response to this
RFA. An applicant may request a project period of up tosevenyears. During the first year of the Network, it
is estimated that the award for the DCC will be approximately $600,000 in
direct costs (no more than $1,020,000 in total costs). The awards to each
CC and to the virology and immunology centers will be approximately $110,000 in
direct costs (no more than $165,000 in total costs). In years 2-7 of the
Network, the amount awarded to each CC per year will vary between $200,000 to $300,000
in direct costs (no more than $450,000 in total costs); to the Immunology and
the Virology Centers between $250,000 to $330,000 in direct costs (no more than
$500,000 in total costs); and to the DCC up to $1,000,000 in direct costs (no
more than $1,500,000 total costs) per year.

Because the nature and
scope of the proposed research will vary from application to application, it is
anticipated that the size and duration of each award will also vary. Although
the financial plans of the IC(s) provide support for this program, awards
pursuant to this funding opportunity are contingent upon the availability of
funds and the receipt of a sufficient number of meritorious applications.

Facilities and
administrative costs requested by consortium participants are not included in
the direct cost limitation, see NOT-OD-05-004.

Section
III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an)
application(s) if your organization has any of the following characteristics:

*Foreign institutions must be located within North
America (Mexico or Canada).

1.B. Eligible Individuals Any individual with the
skills, knowledge, and resources necessary to carry out the proposed research
is invited to work with their institution to develop an application for
support. Individuals from underrepresented racial and ethnic groups as well as
individuals with disabilities are always encouraged to apply for NIH support.

More than one PD/PI, or multiple PDs/PIs, may be
designated on the application for projects that require a “team
science” approach that clearly does not fit the single-PD/PI
model. Additional information on the implementation plans and policies and
procedures to formally allow more than one PD/PI on individual research
projects is available at http://grants.nih.gov/grants/multi_pi.

The
PI of the Data Coordinating Center can be from the same institution as a Clinical Center or the Virology Center or Immunology Center but the PI of the Data Coordinating Center cannot serve as a PI of the Clinical Center or Virology Center or Immunology Center. In contrast, a PI of a Clinical Center can serve as the PI
of the Virology Center or Immunology Center. The Virology Center and Immunology Center can be at the same
institution but must have separate PI’s.

Additionally, due to organizational logistic constraints,
applications will be limited from institutions located with in the United States, Mexico and Canada. The NIH wishes to recruit a diverse patient study population
and will seek geographically diverse Clinical Centers for the Network.
Clinical Centers may bridge up to two hospitals or institutions in a defined
geographic or metropolitan area through subcontracts or a multiple PI
application. Multiple PI applications spanning more than one institution
must document evidence of close collaboration among the PI’s.
NOT-OD-07-017 delineates further details concerning multiple PI applications
and can be found at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-017.html.

Applications must be
prepared using the most current PHS 398 research grant application instructions
and forms. Applications must have a D&B Data Universal Numbering System
(DUNS) number as the universal identifier when applying for Federal grants or
cooperative agreements. The D&B number can be obtained by calling (866)
705-5711 or through the web site at http://www.dnb.com/us/.
The D&B number should be entered on line 11 of the face page of the PHS 398
form.

The title and number of this funding opportunity must
be typed on line 2 of the face page of the application form and the YES box
must be checked.

Foreign Organizations

Several special provisions apply to applications
submitted by foreign organizations:

Request budgets in U.S. dollars.

Prepare detailed budgets for all applications
(that is, complete the Research & Related Budget component of the
SF424 (R&R) application forms – not the PHS398 Modular Budget
component). See NOT-OD-06-096.

Charge back of customs and import
fees is not allowed.

U.S. Government grants cannot pay
taxes in foreign countries, including VAT tax.

Format: Every effort should be
made to comply with the format specifications, which are based upon a
standard U.S. paper size of 8.5” x 11” within each PDF.

Funds for up to 8% administrative
costs (excluding equipment) may be requested. SeeNOT-OD-01-028, March 29,
2001.

Organizations must comply with
Federal/NIH policies on human subjects, animals, and biohazards.

Organizations must comply with
Federal/NIH biosafety and biosecurity regulations. See Section
VI.2., “Administrative and National Policy Requirements.”

Proposed research should provide special opportunities
for furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions in other countries that are not
readily available in the United States or that augment existing U.S. resources.

3. Submission Dates and Times

Applications must be
received on or before the receipt date described below (Section
IV.3.A). Submission times N/A.

Prospective applicants
are asked to submit a letter of intent that includes the following information:

Descriptive title of proposed research

Name, address, and telephone number of the Principal
Investigator

Names of other key personnel

Participating institutions

Number and title of this funding opportunity

Although a letter of
intent is not required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows IC staff to
estimate the potential review workload and plan the review.

The
letter of intent is to be sent by the date listed at the beginning of this
document.

Applications must be
prepared using the research grant applications found in the PHS 398
instructions for preparing a research grant application. Submit a signed,
typewritten original of the application, including the checklist, andthreesigned photocopies in one
package to:

Using the RFA Label: The RFA label available in
the PHS 398 application instructions must be affixed to the bottom of the face
page of the application. Type the RFA number on the label. Failure to use this
label could result in delayed processing of the application such that it may
not reach the review committee in time for review. In addition, the RFA title
and number must be typed on line 2 of the face page of the application form and
the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application
Processing

Applications must be received on or before the
application receipt date(s) described above (Section IV.3.A.).
If an application is received after that date, it will be returned to the
applicant without review. Upon receipt, applications will be evaluated for
completeness by the CSR and responsiveness by theNational
Institute of Diabetes and Digestive and Kidney Diseases.Incomplete and non-responsive
applications will not be reviewed.

The NIH will not accept
any application in response to this funding opportunity that is essentially the
same as one currently pending initial review, unless the applicant withdraws
the pending application. However, when a previously unfunded application,
originally submitted as an investigator-initiated application, is to be
submitted in response to a funding opportunity, it is to be prepared as a NEW
application. That is, the application for the funding opportunity must not
include an Introduction describing the changes and improvements made, and the
text must not be marked to indicate the changes from the previous unfunded
version of the application.

All NIH awards are subject
to the terms and conditions, cost principles, and other considerations
described in the NIH Grants Policy Statement. The Grants Policy Statement can
be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-award costs are
allowable. A grantee may, at its own risk and without NIH prior approval, incur
obligations and expenditures to cover costs up to 90 days before the beginning
date of the initial budget period of a new or competing continuation award if
such costs: are necessary to conduct the project, and would be allowable under
the grant, if awarded, without NIH prior approval. If specific expenditures
would otherwise require prior approval, the grantee must obtain NIH approval before
incurring the cost. NIH prior approval is required for any costs to be incurred
more than 90 days before the beginning date of the initial budget period of a
new or competing continuation award.

The incurrence of
pre-award costs in anticipation of a competing or non-competing award imposes
no obligation on NIH either to make the award or to increase the amount of the
approved budget if an award is made for less than the amount anticipated and is
inadequate to cover the pre-award costs incurred. NIH expects the grantee to be
fully aware that pre-award costs result in borrowing against future support and
that such borrowing must not impair the grantee's ability to accomplish the
project objectives in the approved time frame or in any way adversely affect
the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

6. Other Submission Requirements

To promote
development of a collaborative program, the issues discussed below need to be
addressed in each application for a CC within the Network. This material
is in addition to the submission of a research plan, as described in the
section entitled Research Scope.

o
Qualifications and experience. Applicants for CCs must demonstrate
experience and expertise to conduct clinical studies in hepatitis B. This must
include documentation of experience in the diagnosis and management of patients
with hepatitis B. Inclusion of an expert hepatic pathologist as a collaborator
in the CC application is favorable but not an absolute requirement.

o
Study population. CCs must discuss the number of patients with hepatitis
B seen and followed at the center who might be eligible to enroll in
protocols. The applicant for a CC in the Network must include a
description of the pool of potential study participants by sex, age categories,
and ethnic/racial distribution, as well as recruitment source. Patient access
may be developed by establishing links with other groups outside the CC's
institution. If outside links are proposed, there must be a well described plan
to link the individual CCs with community health care providers such as HMOs,
clinics, or private practice physicians to ensure adequate numbers patients for
clinical studies of therapeutic agents and management strategies.

Applicants
for a CC from institutions that have a General Clinical Research Center (GCRC)
funded by the NIH National Center for Research Resources are encouraged to
identify the GCRC as a resource for conducting the proposed research. If
so, a letter of agreement from either the GCRC Project Coordinator or Principal
Investigator should be included with the application.

o
Willingness to participate in the Hepatitis B Clinical Research Network.
The principal investigator should state his/her general support of
collaborative research and interaction with the NIDDK, the other CCs, Virology Center, Immunology Center, and the DCC through the Network concept. Applicants should discuss
their willingness, and that of the institutions involved, to pursue a per
patient basis (capitation) of operational costs for each protocol. CCs must be
able to interact with the DCC to transmit and edit data and should discuss their
capability to participate in a distributed data entry system.

o
Institutional resources for patient care and follow-up including personnel,
space, and special laboratory facilities should be described.

Applications
for a Virology Center and Immunology Center:

Principal Investigators of the Virology Center and Immunology Center should state his/her general support of collaborative research and
to communicate with the DCC and the NIDDK Project Scientist on a regular
basis. All Principal Investigators must agree to implement the
protocol and manual of operations that will be developed cooperatively and
agree to transmit all study data to the DCC for combination and analysis.
These studies will address virological, immunological, pharmacological and host
factors that might explain the nature of viral and immunopathogenesis of
chronic hepatitis B. The PIs of the Virology Center and Immunology Center will participate in the protocol design and set up the important
collaborations and arrangements with the CCs that will be needed to carry out
the analyses of viral and host factors that correlate with chronic hepatitis B
immunologic and viral status.

Principal Investigators of the Virology Center and Immunology Center will be expected to perform hypothesis-driven laboratory research
on serum and/or tissue samples from patients participating in the
Network. The PIs will direct all technical help and participate in the
completion of planned experiments. The PIs will be expected to report
results regularly and provide results to the DCC for analysis with respect to
the clinical and other virological and immunological features of individual
patients.

The Principal Investigators of the Virology Center and Immunology Center are expected to complete the planned experiments in a timely
fashion and help analyze and prepare the findings for publication.

Applications
for a DCC:

o
Qualifications and experience. The applicant for a DCC must demonstrate
experience in the area of coordinating multi-center clinical trials and
epidemiological studies in all phases: protocol and manual of operations
development, staff training in study procedures, research instrument
development, data collection and management, quality assurance, data analysis,
distributed data entry, electronic communications, administrative management
and coordination. Specific experience in coordinating or monitoring studies of
liver disease is not required, but the applicant may wish to include a
hepatologist or hepatic pathologist in the application as a key collaborator
and advisor.

o
Study design and management. DCC proposals should discuss the applicant's
familiarity and experience with various aspects of study design that would be
important in developing clinical protocols, for example: eligibility criteria;
baseline and outcome measures; methods of randomization; important
considerations for making sample size and power calculations; methods and
frequency of data collection and entry; monitoring accuracy of data collection;
quality control procedures including training and certification for multiple
protocols, some of which may occur simultaneously; managing labeling and
handling of serum and tissue samples (see below); and plans for statistical
analysis. The DCC proposal should also describe their familiarity with model
plans for managing the Data and Safety Monitoring Board. Approximately $70,000
for the whole 7 years should be budgeted for managing the Data and Safety
Monitoring Board.

o
The applicant for the DCC should delineate how laboratory specimens will be
handled. NIDDK anticipates that some clinical outcome measures may be
centrally assessed. Laboratories responsible to the DCC will manage
specimens and laboratory studies as required by the Steering Committee.
The costs of performing specific laboratory tests will be budgeted as a part of
the per patient costs of each CC. The costs of specimen shipment as well as
laboratory data acquisition and management will be a part of the budget of the
DCC. The DCC does not need to prepare two protocols. Estimated shipping
and handling costs for specimens should be included in the budget of DCC.

BUDGET
AND RELATED ISSUES

Applicants
should complete the budget information as directed in the PHS 398 application
form.

Applications
for CCs

Applicants
for the CC should prepare budgets for seven 12-month periods. CCs should
consider the following additional issues regarding budgets. The
underlying concept of theHepatitis
B Clinical Research Network is that a core effort is essential to maintain
the infrastructure required to perform multiple clinical trials or clinical
studies. Based on this approach, it is estimated that the individual CCs
will require a minimum level of effort to sustain the organizational aspects of
the Network. Therefore, individual CCs should submit requests that will
cover a minimum of ten percent effort for the principal investigator, and a
small percent effort for other key personnel (nurse, technician, clinic
coordinator, secretary), and travel costs for two people to attend up to six
Hepatitis B Clinical Research Network meetings during the first year and two to
four times a year thereafter in Bethesda, MD. These costs should be
justified appropriately in budgets and may be distributed into
subcontracts.

In
addition to the core budget, each CC will be provided funds for implementation
of protocols. The precise number of protocols conducted will be
determined by the Hepatitis B Clinical Research Network Steering Committee and
will depend on availability of funds. It is anticipated that after the
first year, two to four protocols may be active each year. CCs may
request PATIENT CARE costs. This amount should be placed in the patient
care category. Allowable total costs for each CC (core costs, costs per
patient to conduct the protocols, and indirect costs) will vary.

The
CCs are requested to present the following information:

The
budget for each clinical protocol should be developed on a cost per patient
basis and include all direct and any applicable facilities and administrative
costs. Costs of laboratory tests should be part of the per patient cost of
conducting a protocol. The clinical protocol should identify the
potential source(s) for any drugs or substances that are being considered for
clinical protocols that are currently unavailable commercially.
Investigators should only prepare budgets for their own CC to conduct the
proposed study or trial, and not for the entire Hepatitis B Clinical Research
Network. The CC should state the total number of patients required by the
entire Network to complete each proposed study or trial. The yearly
budget for each CC should include the number of patients available for the
proposed protocol at that CC. A budget based on the costs per patient for
recruiting and maintaining the specified number of subjects at the applicant's
center should be included for each protocol.

Note
that ongoing annual budgets for protocols will be based on the protocols
approved by the Hepatitis B Clinical Research Network Steering Committee and
will be funded through a per patient basis (capitation) funding
mechanism. The individual CCs will be expected to project patient
enrollment for a specific protocol during a specified time frame; continuation
and level of funding for each CC will be based on actual recruitment and
overall performance.

The
Hepatitis B Clinical Research Network awards will be subject to administrative
review annually.

Virology Center and Immunology Center Budget:

Applicants
for either the Virology Center or Immunology Center should prepare budgets for seven 12-month periods that correspond with the
scientific endeavors proposed and within the budgetary guidelines outlined in
other sections of this RFA. PIs for the Virology Center and Immunology Center are essential to Hepatitis B Clinical Research Network and a core level of
effort commensurate to the scientific proposals and activities of the
consortium will maintain the Network environment. Travel costs should be
requested in the application for two people to attend up to six Hepatitis B
Clinical Research Network steering committee meetings during the first year and
two to four times a year thereafter in Bethesda, MD.

The Immunology Center and Virology Center will be subject to administrative review
annually.

DCC
Budget:

Applicants
for the DCC should prepare budgets for seven 12-month periods that roughly
correspond with the standard coordinating center responsibilities outlined in
other sections of this RFA. In the first year, DCC applicants should
include all costs associated with the organization of all administrative
aspects of the Hepatitis B Clinical Research Network to be developed and with
the initiation of one protocol to be developed and started. For
subsequent years, applicants may assume that two to four protocols a year will
be active, i.e. either in the protocol development, implementation, or analysis
and writing phase. DCC should include costs for managing the Data and Safety
Monitoring Board including the cost of meeting three times/year in Bethesda.

The
DCC will be subject to administrative review annually. It is expected that all
protocols will be performed in a manner consistent with United States Food and
Drug Administration guidelines.

Applications not conforming to these guidelines will be
considered unresponsive to this RFA and will be returned without further
review.

Plan for Sharing Research
Data

All applicants must
include a plan for sharing research data in their application. The data sharing
policy is available at http://grants.nih.gov/grants/policy/data_sharing.
All investigators responding to this funding opportunity should include a
description of how final research data will be shared, or explain why data
sharing is not possible.

The reasonableness of
the data sharing plan or the rationale for not sharing research data will be
assessed by the reviewers. However, reviewers will not factor the proposed data
sharing plan into the determination of scientific merit or the priority score.

The adequacy of the resources sharing plan and any
related data sharing plans will be considered by Program staff of the funding
organization when making recommendations about funding applications. The
effectiveness of the resource sharing will be evaluated as part of the
administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm).
See Section VI.3. Reporting.

Section
V. Application Review Information

1. Criteria

Only the review criteria
described below will be considered in the review process.

The following will be
considered in making funding decisions:

Scientific
merit of the proposed project as determined by peer review

Availability
of funds

Relevance
of program priorities

2. Review and Selection Process

Applications that are
complete and responsive to the RFA will be evaluated for scientific and
technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria
stated below.

As part of the initial
merit review, all applications will:

Undergo a
selection process in which only those applications deemed to have the
highest scientific merit, generally the top half of applications under
review, will be discussed and assigned a priority score.

Receive a
written critique.

Receive a
second level of review by National Institute of Diabetes and Digestive and Kidney Diseases
Advisory Council.

The goals of NIH
supported research are to advance our understanding of biological systems, to
improve the control of disease, and to enhance health. In their written
critiques, reviewers will be asked to comment on each of the following criteria
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals. Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application. Note that an application does not need to be
strong in all categories to be judged likely to have major scientific impact
and thus deserve a high priority score. For example, an investigator may
propose to carry out important work that by its nature is not innovative but is
essential to move a field forward.

Significance: Does this study address an
important problem? If the aims of the application are achieved, how will
scientific knowledge or clinical practice be advanced? What will be the effect
of these studies on the concepts, methods, technologies, treatments, services,
or preventative interventions that drive this field?

Approach: Are the conceptual or
clinical framework, design, methods, and analyses adequately developed, well
integrated, well reasoned, and appropriate to the aims of the project? Does the
applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and
innovative? For example: Does the project challenge existing paradigms or
clinical practice; address an innovative hypothesis or critical barrier to
progress in the field? Does the project develop or employ novel concepts,
approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators
appropriately trained and well suited to carry out this work? Is the work
proposed appropriate to the experience level of the principal investigator and
other researchers? Does the investigative team bring complementary and
integrated expertise to the project (if applicable)? For
applications designating multiple PDs/PIs, does the Leadership Plan ensure that
there will be sufficient coordination and communication among the
PDs/PIs? Are the administrative plans for the management of the research
project appropriate, including plans for resolving conflicts?

Environment: Does the scientific
environment in which the work will be done contribute to the probability of
success? Do the proposed studies benefit from unique features of the scientific
environment, or subject populations, or employ useful collaborative
arrangements? Is there evidence of institutional support?

2.A. Additional Review
Criteria:

In addition to the above
criteria, the following items will continue to be considered in the determination
of scientific merit and the priority score:

Protection
of Human Subjects from Research Risk: The involvement of human subjects and protections from
research risk relating to their participation in the proposed research will be
assessed (see the Research Plan, Section E on Human Subjects in the PHS Form
398).

Inclusion
of Women, Minorities and Children in Research: The adequacy of plans to
include subjects from both genders, all racial and ethnic groups (and
subgroups), and children as appropriate for the scientific goals of the
research will be assessed. Plans for the recruitment and retention of subjects
will also be evaluated (see the Research Plan, Section E on Human Subjects in
the PHS Form 398).

Care and
Use of Vertebrate Animals in Research: If vertebrate animals are to
be used in the project, the five items described under Section F of the PHS
Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures
are proposed that are potentially hazardous to research personnel and/or the
environment, determine if the proposed protection is adequate.

2.B. Additional Review
Considerations

Budget: The reasonableness of the
proposed budget and the requested period of support in relation to the proposed
research. The priority score should not be affected by the evaluation of the
budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the
data sharing plan or the rationale for not sharing research data will be
assessed by the reviewers. However, reviewers will not factor the proposed data
sharing plan into the determination of scientific merit or the priority score.
The presence of a data sharing plan will be part of the terms and conditions of
the award. The funding organization will be responsible for monitoring the data
sharing policy.

Program staff will be
responsible for the administrative review of the plan for sharing research
resources.

The adequacy of the
resources sharing plan will be considered by Program staff of the funding
organization when making recommendations about funding applications. Program
staff may negotiate modifications of the data and resource sharing plans with
the awardee before recommending funding of an application. The final version of
the data and resource sharing plans negotiated by both will become a condition
of the award of the grant. The effectiveness of the resource sharing will be
evaluated as part of the administrative review of each non-competing Grant
Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates

N/A.

Section
VI. Award Administration Information

1. Award Notices

After the peer review of
the application is completed, the PD/PI will be able to access his or her
Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding,
NIH will request "just-in-time" information from the applicant. For
details, applicants may refer to the NIH Grants Policy Statement Part II: Terms
and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

A formal notification in the form of a Notice
of Award (NoA) will be provided to the applicant organization. The NoA
signed by the grants management officer is the authorizing document. Once all
administrative and programmatic issues have been resolved, the NoA will be
generated via email notification from the awarding component to the grantee
business official (designated in item 12 on the Application Face Page). If a
grantee is not email enabled, a hard copy of the NoA will be mailed to the
business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Also Section
IV.5. Funding Restrictions.

The following Terms and
Conditions will be incorporated into the award statement and will be provided
to the Principal Investigator as well as to the appropriate institutional
official, at the time of award.

2.A. Cooperative Agreement
Terms and Conditions of Award

The following special
terms of award are in addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS grant administration regulations at 45 CFR Parts
74 and 92 (Part 92 is applicable when State and local Governments are eligible
to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for
this program will be the cooperative agreement (U01), an
"assistance" mechanism (rather than an "acquisition"
mechanism), in which substantial NIH programmatic involvement with the awardees
is anticipated during the performance of the activities. Under the cooperative
agreement, the NIH purpose is to support and stimulate the recipients'
activities by involvement in and otherwise working jointly with the award
recipients in a partnership role; it is not to assume direction, prime
responsibility, or a dominant role in the activities. Consistent with this
concept, the dominant role and prime responsibility resides with the awardees
for the project as a whole, although specific tasks and activities may be
shared among the awardees and the NIH as defined below. 2.A.1. Principal
Investigator Rights and Responsibilities

The Principal Investigator
will have the primary responsibility for:

The
awardee(s) will have lead responsibilities in all aspects of their protocols,
including any modification of study design, conduct of the study, quality
control, data analysis and interpretation, preparation of publications, and
collaboration with other investigators, unless otherwise provided for in these
terms or by action of the Steering Committee. Awardees will be required
to accept and implement the common protocol(s) and procedures approved by the
Steering Committee. Modifications and ancillary protocols will be
approved by the Steering Committee and the Data and Safety Monitoring Board.

Awardees will retain custody of and have primary rights to
their data developed under these awards, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies. The collaborative
protocol and governance policies will call for the continued submission of data
centrally to the DCC for a collaborative database; the submission of copies of
the collaborative data sets to each principal investigator upon completion of
the study; procedures for data analysis, reporting and publication; and
procedures to protect and ensure the privacy of medical and genetic data (if
any) and records of individuals. The NIDDK Project Scientist, on behalf
of the NIDDK, will have the same access, privileges and responsibilities
regarding the collaborative data as the other members of the Steering
Committee.

Designating Protocol Chairs. The Principal Investigators
(for studies involving multiple coordinated awards) shall designate a single
Protocol Chairperson (if the Principal Investigator does not assume this role)
for each protocol within the described research plan. The Protocol Chairperson
shall function as the scientific coordinator for the protocol and shall assume
responsibility for obtaining approval to implement the protocol from the
Steering Committee and for developing and monitoring the protocol. Any
significant modifications to approved protocols must be submitted to the
Steering Committee by the Protocol Chairperson.

Implementing the core data collection method and strategy
collectively decided upon by the Steering Committee. For a study involving
multiple institutions, it is the responsibility of each awardee/site to ensure
that data will be submitted in a timely way to the central Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the
ability to implement the strategy specifically designed for their individual
study population.

Implementing the core data collection method and strategy
collectively decided upon by the Steering Committee. For a study involving
multiple institutions, it is the responsibility of each awardee/site to ensure
that data will be submitted in a timely way to the central Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the
ability to implement the strategy specifically designed for their individual
study population.

Establishing mechanisms for quality control and monitoring.
Awardees are responsible for ensuring accurate and timely assessment of the
progress of each study, including development of procedures to ensure that data
collection and management are: (1) adequate for quality control and analysis;
(2) for clinical trials, as simple as appropriate in order to encourage maximum
participation of physicians and patients and to avoid unnecessary expense; and
(3) sufficiently staffed across the participating institutions. For research
involving multiple awards, strategies for the analyses of pooled data will be
developed by the Steering Committee.

Submitting interim progress reports, when requested, to the
NIDDK Program Director including as a minimum, summary data on protocol
performance. For coordinated multiple awards or a multi-site single award, the
Steering Committee may require additional information from individual
awardees/sites. Such reports are in addition to the annual awardee noncompeting
continuation progress report

Establishing procedures, where applicable, for all
participating institutions in coordinated awards to comply with FDA regulations
for studies involving investigational agents or devices and to comply with the
requirements of 45 CFR Part 46 for the protection of human subjects, and the
NIH policy requirements for the inclusion of women, minorities and children.

The Data Coordinating Center will be involved in
collaborations with the NIDDK, the Clinical Centers and the Immunology and Virology Centers during all phases of the trial and will maintain the Specimen Core
facility. Thus, the awardee is expected to work cooperatively with
Clinical Centers and sponsoring organizations in a multicenter trial and
oversee the implementation of and adherence to a common protocol, as well as
assure quality control of the data collected and storage of collected tissue
specimens. In addition to organizing and attending regular meetings, the Data Coordinating Center will be expected to maintain close communications with the NIDDK
Project Scientist and the Principal Investigators of the Clinical Centers.

Awardees are encouraged to publish and to publicly release
and disseminate results, data and other products of the study, concordant with
the study protocol and governance and the approved plan for making data and
materials available to the scientific community and the NIDDK. However,
during or within three years beyond the end date of the project period of NIDDK
support, unpublished data, unpublished results, data sets not previously
released, or other study materials or products are to be made available to any
third party only with the approval of the Steering Committee.

Support or other involvement of industry or any other third
party in any study performed by the Network -- e.g., participation by the third
party; involvement of project resources or citing the name of the project or
the NIDDK support; or special access to project results, data, findings or
resources -- may be advantageous and appropriate. However, except for
licensing of patents or copyrights, support or involvement of any third party
will occur only following notification to, and concurrence by, NIDDK.

Upon completion of the project, the DCC is expected to put
all study intervention materials and procedure manuals into the public domain
and/or make them available to other investigators, according to the approved
plan for making data and materials available to the scientific community and
the NIDDK, for the conduct of research at no charge other than the costs of reproduction
and distribution.

The NIDDK has established Central Biosample, Genetic, and
Data Repositories for the archival and storage of data and biosamples collected
in large, multi-site studies funded by NIDDK. The Data Coordinating Center
(DCC) will work with the NIDDK Biosample Repository to coordinate procedures
for coding, shipping, processing, receipt, and storage of study samples that
are to be maintained in the Repository. In addition, the DCC will coordinate
with the NIDDK Data Repository to prepare the collected data for eventual
archiving and distribution. All samples and data transferred to the
Repositories will be under the custodianship of the NIDDK, although the study's
Steering Committee will have proprietary control of and exclusive access to the
samples and data for an agreed-upon period of time. Subsequently samples and
data will be available to the wider scientific community in accordance with the
NIH policy on Data Sharing ( http://grants.nih.gov/grants/policy/data_sharing/ and, http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm)
through a process that will include prioritized distribution based on review of
the scientific merit of the proposed use. Therefore, it is expected that
samples and data collected will be available to the broader scientific
community, after a proprietary period, at no charge other than the cost of
reproduction and distribution.

Awardees
will retain custody of and have primary rights to the data and software
developed under these awards, subject to Government rights of access consistent
with current HHS, PHS, and NIH policies.

2.A.2. NIH
Responsibilities

An NIH Project Scientist
will have substantial programmatic involvement that is above and beyond the
normal stewardship role in awards, as described below.
The
NIDDK will name a Project Scientist from within the Division of Digestive

Diseases and Nutrition whose function will be to assist the
Steering Committee in carrying out the study. The Project Scientist will
have one vote for all key study group subcommittees. The Project
Scientist will have substantial scientific-programmatic involvement in quality
control, interim data analysis, safety monitoring, and final data analysis and
interpretation, preparation of publications, and coordination and performance
monitoring. The dominant role and prime responsibility for these
activities resides with the awardees for the project as a whole, although specific
tasks and activities in carrying out the studies will be shared among the
awardees and the NIDDK Project Scientist.

The NIDDK reserves the right to terminate or curtail the
study (or an individual award) in the event of (a) failure to develop or
implement a mutually agreeable collaborative protocol, (b) substantial
shortfall in participant recruitment, follow-up, data reporting, quality
control, or other major breach of the protocol, (c) substantive changes in the
agreed-upon protocol with which NIDDK cannot concur, (d) reaching a major study
endpoint substantially before schedule with persuasive statistical
significance, or (e) human subject ethical issues that may dictate a premature
termination.

Other NIDDK Project Scientist
responsibilities and levels of involvement in the project, as described below.

For multi-institutional protocols, convening the first
meeting of and subsequent participation in the Steering Committee that oversees
study conduct. The NIDDK Project Scientist or designee will be a full
participant and voting member of the Steering Committee and, if applicable,
subcommittees.

Serving as a resource with respect to other ongoing NIDDK
activities that may be relevant to the protocol to facilitate compatibility and
avoid unnecessary duplication of effort.

Substantial involvement assisting in the design and
coordination of research activities for awardees as elaborated below:

Assisting by providing advice in the management and
technical performance of the investigations, coordinating clearances for
investigational agents held by NIDDK. The NIDDK may reserve the right to cross
file or independently file an Investigational New Drug Application form with
the FDA.

For multi-institutional protocols, through participation in
the Steering Committee and with the agreement of the Principal Investigator(s)
of any coordinating center and data management centers, the NDDK Project
Scientist or designee may coordinate activities among awardees by assisting in
the design, development, and coordination of a common research or clinical
protocol and statistical evaluations of data; in the preparation of
questionnaires and other data recording forms; and in the publication of
results.

Reviewing and approving advice regarding the establishment
of mechanisms for quality control and study monitoring.

An NIDDK Program Director identified in the Notice of Grant
Award will be responsible for the normal stewardship and monitoring of the
award. The Program Director may also serve as the Project Scientist.

The NIDDK Program Director
responsibilities include:

Retaining overall programmatic responsibility for the
award, and will clearly specify to the awardee the name(s) and role (s) of any
additional individuals with substantial involvement in the project and the lines
of reporting authority.

Interacting with the principal investigator(s) on a regular
basis to monitor study progress. Monitoring may include: regular communications
with the principal investigator and staff, periodic site visits for discussions
with awardee research teams, observation of field data collection and
management techniques, quality control, fiscal review, and other relevant
matters; as well as attendance at Steering Committee, data safety and
monitoring board, and related meetings. The NIDDK retains, as an option,
periodic external review of progress.

Reviewing and approving protocols to insure they are within
the scope of peer review and for safety considerations, as required by Federal
regulations. The NIDDK Program Director will monitor protocol progress, and may
request that a protocol study be closed to accrual for reasons including: (a)
accrual rate insufficient to complete study in a timely fashion; (b) accrual
goals met early; (c) poor protocol performance; (d) patient safety and regulatory
concerns; (e) study results that are already conclusive; and (f) emergence of
new information that diminishes the scientific importance of the study
question. The NIDDK will not permit further expenditures of NIDDK funds for a
study after requesting closure (except for patients already on-study).

Making recommendations for continued funding based on: a)
overall study progress, including sufficient patient and/or data accrual; b)
cooperation in carrying out the research (e.g., attendance at Steering
Committee meetings, implementation of group decisions, compliance with the
terms of award and reporting requirements); and/or c) maintenance of a high
quality of research, which will allow pooling of data and comparisons across
multiple cooperative agreement awards for common data elements.

Additionally, an agency
program official or IC program director will be responsible for the normal
scientific and programmatic stewardship of the award and will be named in the
award notice.

2.A.3. Collaborative
Responsibilities

The
Steering Committee, composed of each of the Principal Investigators (or the
corresponding PI from a multiple PI application) of the DCC, the Virology
Center, the Immunology Center, and the CCs, the NIDDK Project Scientist and
others from the DCC, the clinical sites and the NIDDK as deemed necessary will
be the main governing board of the studies. However, only the principal
investigators (or the corresponding PI from a multiple PI application) and the
NIDDK Project Scientist or designee will be voting members of the Steering
Committee and all major scientific decisions will be determined by a majority
vote. This committee will have the primary responsibility for approval of
the common protocols, facilitating the conduct of participant follow-up,
monitoring completeness of data collection and timely transmission of data to
the DCC, and reporting the study results. It will also be responsible for
establishing study policies in such areas as access to patient data, ancillary
studies, publications and presentations, and performance standards. A
Chairperson will be chosen from among the Steering Committee members by the
NIDDK program director from among the principal investigators (but not the
NIDDK Project Scientist or Data Coordinating Center Principal
Investigator). The Chairperson is responsible for coordinating the
Committee activities, for preparing meeting agendas, and for scheduling and
chairing meetings. Subcommittees will be established on topics such as
ancillary studies, publications and presentations, quality control,
recruitment, protocol adherence, among others.

Each Network Awardee and the DCC Awardee agree to the
governance of the study through the Steering Committee. Meetings of the
Steering Committee will ordinarily be held by telephone conference calls or in
the Washington DC Metropolitan Area.

An independent Data and Safety Monitoring Board will
be established by the NIDDK. The Data and Safety Monitoring Board will review
interim results periodically as established in the data and safety monitoring
plan and report to the NIDDK program director. The NIDDK Program Director will
report in writing to the Steering Committee on the recommendations of the DSMB
and the NIDDK concurrence/non-concurrence of the DSMB recommendations. The
principal investigators will assume responsibility for reporting of the DSMB
and the NIDDK recommendations to their respective Institutional Review Boards.

The NIDDK Project Scientist (and the other cited NIDDK
scientists) may work with awardees on issues coming before the Steering
Committee and, as appropriate, other committees, e.g., issues of recruitment,
intervention, follow-up, quality control, standards and methods, adherence to
protocol, assessment of problems affecting the study and potential changes in
the protocol, interim data and safety monitoring, final data analysis and
interpretation, preparation of publications, and development of solutions to
major problems such as insufficient participant enrollment. Regardless of
the number of NIH staff participating in technical advisory roles, the NIDDK
will be limited to one vote on the Steering Committee.

Each full member will
have one vote. Awardee members of the Steering Committee will be required to
accept and implement policies approved by the Steering Committee.

2.A.4. Arbitration
Process

Any disagreements that
may arise in scientific or programmatic matters (within the scope of the award)
between award recipients and the NIH may be brought to arbitration. An
Arbitration Panel composed of three members will be convened. It will have
three members: a designee of the Steering Committee chosen without NIH staff
voting, one NIH designee, and a third designee with expertise in the relevant
area who is chosen by the other two; in the case of individual disagreement,
the first member may be chosen by the individual awardee. This special
arbitration procedure in no way affects the awardee's right to appeal an
adverse action that is otherwise appealable in accordance with PHS regulations
42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

We
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research, peer review, and financial or grants
management issues:

Human Subjects
Protection:Federal regulations
(45CFR46) require that applications and proposals involving human subjects must
be evaluated with reference to the risks to the subjects, the adequacy of
protection against these risks, the potential benefits of the research to the
subjects and others, and the importance of the knowledge gained or to be gained
(http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety
Monitoring Plan:Data and safety
monitoring is required for all types of clinical trials, including physiologic
toxicity and dose-finding studies (phase I); efficacy studies (Phase II);
efficacy, effectiveness and comparative trials (Phase III). Monitoring should
be commensurate with risk. The establishment of data and safety monitoring
boards (DSMBs) is required for multi-site clinical trials involving
interventions that entail potential risks to the participants (NIH Policy for
Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research
Data:Investigators submitting
an NIH application seeking $500,000 or more in direct costs in any single year
are expected to include a plan for data sharing or state why this is not
possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their
institutions, on issues related to institutional policies and local IRB rules,
as well as local, State and Federal laws and regulations, including the Privacy
Rule. Reviewers will consider the data sharing plan but will not factor the
plan into the determination of the scientific merit or the priority score.

Access to Research
Data through the Freedom of Information Act:The Office of Management
and Budget (OMB) Circular A-110 has been revised to provide access to research
data through the Freedom of Information Act (FOIA) under some circumstances.
Data that are (1) first produced in a project that is supported in whole or in
part with Federal funds and (2) cited publicly and officially by a Federal
agency in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for applicants to
understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Sharing of Model
Organisms:NIH is committed to
support efforts that encourage sharing of important research resources
including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to
elect and retain title to subject inventions developed with Federal funding
pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm).
All investigators submitting an NIH application or contract proposal, beginning
with the October 1, 2004 receipt date, are expected to include in the
application/proposal a description of a specific plan for sharing and
distributing unique model organism research resources generated using NIH
funding or state why such sharing is restricted or not possible. This will
permit other researchers to benefit from the resources developed with public
funding. The inclusion of a model organism sharing plan is not subject to a
cost threshold in any year and is expected to be included in all applications
where the development of model organisms is anticipated.

Inclusion of Women
And Minorities in Clinical Research:It is the policy of the
NIH that women and members of minority groups and their sub-populations must be
included in all NIH-supported clinical research projects unless a clear and
compelling justification is provided indicating that inclusion is inappropriate
with respect to the health of the subjects or the purpose of the research. This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43). All investigators proposing clinical research should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children
as Participants in Clinical Research:The NIH maintains a
policy that children (i.e., individuals under the age of 21) must be included
in all clinical research, conducted or supported by the NIH, unless there are
scientific and ethical reasons not to include them.

Required Education on
the Protection of Human Subject Participants:NIH policy requires
education on the protection of human subject participants for all investigators
submitting NIH applications for research involving human subjects and
individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem
Cells (hESC):Criteria for federal
funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only research using hESC lines that are registered in the NIH Human Embryonic
Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility
of the applicant to provide in the project description and elsewhere in the
application as appropriate, the official NIH identifier(s) for the hESC
line(s)to be used in the proposed research. Applications that do not provide
this information will be returned without review.

NIH Public Access
Policy:NIH-funded investigators
are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central
(PMC) an electronic version of the author's final manuscript upon acceptance
for publication, resulting from research supported in whole or in part with
direct costs from NIH. The author's final manuscript is defined as the final
version accepted for journal publication, and includes all modifications from
the publishing peer review process.

NIH is requesting that
authors submit manuscripts resulting from 1) currently funded NIH research
projects or 2) previously supported NIH research projects if they are accepted
for publication on or after May 2, 2005. The NIH Public Access Policy applies
to all research grant and career development award mechanisms, cooperative
agreements, contracts, Institutional and Individual Ruth L. Kirschstein
National Research Service Awards, as well as NIH intramural research studies.
The Policy applies to peer-reviewed, original research publications that have
been supported in whole or in part with direct costs from NIH, but it does not
apply to book chapters, editorials, reviews, or conference proceedings.
Publications resulting from non-NIH-supported research projects should not be
submitted.

Standards for Privacy
of Individually Identifiable Health Information:The Department of Health
and Human Services (DHHS) issued final modification to the "Standards for
Privacy of Individually Identifiable Health Information", the
"Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal
regulation under the Health Insurance Portability and Accountability Act
(HIPAA) of 1996 that governs the protection of individually identifiable health
information, and is administered and enforced by the DHHS Office for Civil
Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and
research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant
Applications or Appendices:
All applications and proposals
for NIH funding must be self-contained within specified page limitations. For
publications listed in the appendix and/or Progress report, internet addresses
(URLs) must be used for publicly accessible on-line journal
articles. Unless otherwise specified in this solicitation,
Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation
to view the Internet sites. Furthermore, we caution reviewers that their
anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:The Public Health
Service (PHS) is committed to achieving the health promotion and disease
prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This RFA is related to one or more of the
priority areas. Potential applicants may obtain a copy of "Healthy People
2010" at http://www.health.gov/healthypeople.

Authority and
Regulations:This program is described
in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is
not subject to the intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review. Awards are made under the authorization
of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241
and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
All awards are subject to the terms and conditions, cost principles, and other
considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly
encourages all grant recipients to provide a smoke-free workplace and
discourage the use of all tobacco products. In addition, Public Law 103-227,
the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in
some cases, any portion of a facility) in which regular or routine education,
library, day care, health care, or early childhood development services are provided
to children. This is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.

Loan Repayment
Programs:NIH encourages
applications for educational loan repayment from qualified health professionals
who have made a commitment to pursue a research career involving clinical,
pediatric, contraception, infertility, and health disparities related areas.
The LRP is an important component of NIH's efforts to recruit and retain the
next generation of researchers by providing the means for developing a research
career unfettered by the burden of student loan debt. Note that an NIH grant is
not required for eligibility and concurrent career award and LRP applications
are encouraged. The periods of career award and LRP award may overlap providing
the LRP recipient with the required commitment of time and effort, as LRP
awardees must commit at least 50% of their time (at least 20 hours per week
based on a 40 hour week) for two years to the research. For further
information, please see: http://www.lrp.nih.gov.